FOXP1 Research Articles

Mapping of Human FOXP2 Enhancers Reveals Complex Regulation.

Mutations of the FOXP2 gene cause a severe speech and language disorder, providing a molecular window into the neurobiology of language. Individuals with FOXP2 mutations have structural and functional alterations affecting brain circuits that overlap with sites of FOXP2 expression, including regions of the cortex, striatum, and cerebellum. FOXP2 displays complex patterns of expression in the brain, as well as in non-neuronal tissues, suggesting that sophisticated regulatory mechanisms control its spatio-temporal expression. However, to date, little is known about the regulation of FOXP2 or the genomic elements that control its expression. Using chromatin conformation capture (3C), we mapped the human FOXP2 locus to identify putative enhancer regions that engage in long-range interactions with the promoter of this gene. We demonstrate the ability of the identified enhancer regions to drive gene expression. We also show regulation of the FOXP2 promoter and enhancer regions by candidate regulators – FOXP family and TBR1 transcription factors. These data point to regulatory elements that may contribute to the temporal- or tissue-specific expression patterns of human FOXP2. Understanding the upstream regulatory pathways controlling FOXP2 expression will bring new insight into the molecular networks contributing to human language and related disorders.

Genetic study of the association of specific language impairment to markers near FOXP2 gene

Background One important language gene is FOXP2, a mutation of which affects language and speech in relatively rare and severe forms. However, certain genetic markers adjacent to FOXP2 gene are highly suspected to be involved in common forms of specific language impairment (SLI). Identification of these genetic loci related to SLI may yield new insights into its causes, along with improved diagnosis, and treatment. Aim of the work To study the association of SLI to two genetic markers residing near FOXP2 gene, namely, the repeat unit GATA of D7S3052 marker and GATT tetranucleotide repeats in intron 6 of CFTR gene. Patients and methods The current study included 50 children with SLI and 50 normal controls, aged 3–8 years. All participants were subjected to genetic molecular association study as well as detailed protocol of assessment including full history and examination, and evaluation of language skills and mental ability (intelligence quotient). Results There was no difference between the SLI and normal groups regarding molecular results of GATT repeats of CFTR gene, and there was a nonsignificant difference regarding results of GATA repeats of D7S3052 marker (P > 0.05). Conclusion The association of SLI with D7S3052 marker near FOXP2 gene in current study is statistically nonsignificant. However, a statistical significance of this association could be expected with a larger number of cases, more diversity of SLI types and degrees, and more comprehensive procedures.

Studying the Mechanisms of Developmental Vocal Learning and Adult Vocal Performance in Zebra Finches through Lentiviral Injection.

Here we provide a detailed step-by-step protocol for using lentivirus to manipulate miRNA expression in Area X of juvenile zebra finches and for analyzing the consequences on song learning and song performance. This protocol has four parts: 1) making the lentiviral construct to overexpress miRNA miR-9; 2) packaging the lentiviral vector; 3) stereotaxic injection of the lentivirus into Area X of juvenile zebra finches; 4) analysis of song learning and song performance in juvenile and adult zebra finches. These methods complement the methods employed in recent works that showed changing FoxP2 gene expression in Area X with lentivirus or adeno-associated virus leads to impairments in song behavior.

Circ-SHKBP1 Regulates the Angiogenesis of U87 Glioma-Exposed Endothelial Cells through miR-544a/FOXP1 and miR-379/FOXP2 Pathways.

Circular RNAs (circRNAs) are a type of endogenous non-coding RNAs, which have been considered to mediate diverse tumorigenesis including angiogenesis. The present study aims to elucidate the potential role and molecular mechanism of circ-SHKBP1 in regulating the angiogenesis of U87 glioma-exposed endothelial cells (GECs). The expression of circ-SHKBP1, but not linear SHKBP1, was significantly upregulated in GECs compared with astrocyte-exposed endothelial cells (AECs). circ-SHKBP1 knockdown inhibited the viability, migration, and tube formation of GECs dramatically. The expressions of miR-379/miR-544a were downregulated in GECs, and circ-SHKBP1 functionally targeted miR-544a/miR-379 in an RNA-induced silencing complex (RISC) manner. Dual-luciferase reporter assay demonstrated that forkhead box P1/P2 (FOXP1/FOXP2) were targets of miR-544a/miR-379. The expressions of FOXP1/FOXP2 were upregulated in GECs, and silencing of FOXP1/FOXP2 inhibited the viability, migration, and tube formation of GECs. Meanwhile, FOXP1/FOXP2 promoted angiogenic factor with G patch and FHA domains 1 (AGGF1) expression at the transcriptional level. Furthermore, knockdown of AGGF1 suppressed the viability, migration, and tube formation of GECs via phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK)1/2 pathways. Taken together, the present study demonstrated that circ-SHKBP1 regulated the angiogenesis of GECs through miR-544a/FOXP1 and miR-379/FOXP2 pathways, and these findings might provide a potential target and effective strategy for combined therapy of gliomas.

Phonological working memory and FOXP2

The discovery and description of the affected members of the KE family (aKE) initiated research on how genes enable the unique human trait of speech and language. Many aspects of this genetic influence on speech-related cognitive mechanisms are still elusive, e.g. if and how cognitive processes not directly involved in speech production are affected. In the current study we investigated the effect of the FOXP2 mutation on Working Memory (WM).Half the members of the multigenerational KE family have an inherited speech-language disorder, characterised as a verbal and orofacial dyspraxia caused by a mutation of the FOXP2 gene. The core phenotype of the affected KE members (aKE) is a deficiency in repeating words, especially complex non-words, and in coordinating oromotor sequences generally. Execution of oromotor sequences and repetition of phonological sequences both require WM, but to date the aKE's memory ability in this domain has not been examined in detail.To do so we used a test series based on the Baddeley and Hitch WM model, which posits that the central executive (CE), important for planning and manipulating information, works in conjunction with two modality-specific components: The phonological loop (PL), specialized for processing speech-based information; and the visuospatial sketchpad (VSSP), dedicated to processing visual and spatial information. We compared WM performance related to CE, PL, and VSSP function in five aKE and 15 healthy controls (including three unaffected members of the KE family who do not have the FOXP2 mutation).The aKE scored significantly below this control group on the PL component, but not on the VSSP or CE components. Further, the aKE were impaired relative to the controls not only in motor (i.e. articulatory) output but also on the recognition-based PL subtest (word-list matching), which does not require speech production. These results suggest that the aKE's impaired phonological WM may be due to a defect in subvocal rehearsal of speech-based material, and that this defect may be due in turn to compromised speech-based representations.

Autoimmunity as a Driving Force of Cognitive Evolution.

In the last decades, increasingly robust experimental approaches have formally demonstrated that autoimmunity is a physiological process involved in a large range of functions including cognition. On this basis, the recently enunciated “brain superautoantigens” theory proposes that autoimmunity has been a driving force of cognitive evolution. It is notably suggested that the immune and nervous systems have somehow co-evolved and exerted a mutual selection pressure benefiting to both systems. In this two-way process, the evolutionary-determined emergence of neurons expressing specific immunogenic antigens (brain superautoantigens) has exerted a selection pressure on immune genes shaping the T-cell repertoire. Such a selection pressure on immune genes has translated into the emergence of a finely tuned autoimmune T-cell repertoire that promotes cognition. In another hand, the evolutionary-determined emergence of brain-autoreactive T-cells has exerted a selection pressure on neural genes coding for brain superautoantigens. Such a selection pressure has translated into the emergence of a neural repertoire (defined here as the whole of neurons, synapses and non-neuronal cells involved in cognitive functions) expressing brain superautoantigens. Overall, the brain superautoantigens theory suggests that cognitive evolution might have been primarily driven by internal cues rather than external environmental conditions. Importantly, while providing a unique molecular connection between neural and T-cell repertoires under physiological conditions, brain superautoantigens may also constitute an Achilles heel responsible for the particular susceptibility of Homo sapiens to “neuroimmune co-pathologies” i.e., disorders affecting both neural and T-cell repertoires. These may notably include paraneoplastic syndromes, multiple sclerosis as well as autism, schizophrenia and neurodegenerative diseases. In the context of this theoretical frame, a specific emphasis is given here to the potential evolutionary role exerted by two families of genes, namely the MHC class II genes, involved in antigen presentation to T-cells, and the Foxp genes, which play crucial roles in language (Foxp2) and the regulation of autoimmunity (Foxp3).

Abstract 013: The Molecular Program of Renin Null Cells

Mice homozygous for the Ren1c gene disruption ( Ren1c -/- ) display structural and functional defects characterized by a poorly developed renal medulla, urine concentration failure, polydipsia, polyuria, hydronephrosis, renal failure and anemia. Underlying this complex phenotype, mice exhibit unique renal vascular abnormalities, including concentric arteriolar hypertrophy. Using lineage and promoter activity tracking, we showed that renin null cells contribute directly to blood vessel thickening and distribute throughout renal arterial trees. We hypothesize that renin null cells synthesize factors that lead to arterial thickening and maintain an active molecular memory of the renin phenotype. To test this hypothesis, we performed RNA-seq of YFP sorted single cells from kidneys of Ren1c -/- ; Ren1c -YFP (KO) and Ren1c +/+ ; Ren1c -YFP (wildtype, WT) adult mice. We captured individual cells using a microfluidic C1 system and sequenced cDNA from cellular mRNA. We also performed ATAC-seq of KO cells to identify open chromatin regions available for transcription factor binding. KO and WT cell populations were distinct, with the average Euclidean distance between genotypes 1.9x greater than within genotypes. Differential expression analysis revealed that KO cells upregulated 1395 genes and downregulated 364 compared to WT (log fold change > 1, p < 0.05). Among the upregulated genes were 107 potentially secreted proteins and 64 putative transcription factors. Secreted protein genes were enriched for GO terms such as angiogenesis and cell proliferation (p < 0.01), suggesting a possible cause of arteriolar abnormalities in KO kidneys. We identified several upregulated transcription factors, including Foxp1, Stat1, and KLF family genes, that had predicted binding motifs in open chromatin regions, such as upstream the Ren1 gene (p < 1.0E-10). These factors are key candidates for regulating the molecular memory of the renin cell. This study shows that over activation of the renin program due to lack of renin causes expression of a distinct suite of genes that may be responsible for vascular pathologies observed in KO mice. These data also provide insight into how the cell regulates the renin cell program in response to chronic stimuli that jeopardize homeostasis.

Upregulation of microRNA-206 induces apoptosis of vascular smooth muscle cells and decreases risk of atherosclerosis through modulating FOXP1.

Forkhead box protein subfamily P (FOXP) 1 has an important role in the control of gene transcription and is also reported to function as a tumor suppressor. The aim of the present study was to explore the regulatory mechanisms of atherosclerosis by investigating the function of microRNA-206 (miR-206) and the regulatory association between miR-206 and its potential target gene, FOXP1, in vascular smooth muscle cells (VSMCs). Bioinformatics tools were utilized to identify FOXP1 as a target of miR-206. Luciferase reporter analysis was used to confirm this relationship and to identify the miR-206 binding site in the FOXP1 3′-untranslated region. It was demonstrated that the relative survival rate of VSMCs was suppressed by miR-206 compared with scramble controls. Furthermore, reduced expression of miR-206 in atherosclerosis tissue samples was observed, and the mRNA and protein expression levels of FOXP1 were upregulated in atherosclerosis tissue samples, both compared with the controls, indicating a negative correlation between miR-206 and FOXP1. Additionally, when treated with miR-206 mimics, the relative survival rate of VSMCs was notably reduced, which was rescued by overexpression of FOXP1. These findings increased the understanding of the regulatory role of miR-206 in atherosclerosis in VSMCs via targeting the FOXP1 gene; therefore, intervention with miR-206 as a therapeutic technique may be a strategy for atherosclerosis treatment in the future.

A common genetic variant in FOXP2 is associated with language-based learning (dis)abilities: Evidence from two Italian independent samples.

Language-based Learning Disabilities (LLDs) encompass a group of complex, comorbid, and developmentally associated deficits in communication. Language impairment and developmental dyslexia (DD) represent the most recognized forms of LLDs. Substantial genetic correlations exist between language and reading (dis)abilities. Common variants in the FOXP2 gene were consistently associated with language- and reading-related neuropsychological and neuroanatomical phenotypes. We tested the effect of a FOXP2 common variant, that is, rs6980093 (A/G), on quantitative measures of language and reading in two independent Italian samples: a population-based cohort of 699 subjects (3-11 years old) and a sample of 572 children with DD (6-18 years old). rs6980093 modulates expressive language in the general population sample, with an effect on fluency scores. In the DD sample, the variant showed an association with the accuracy in the single word reading task. rs6980093 shows distinct genetic models of association in the two cohorts, with a dominant effect of the G allele in the general population sample and heterozygote advantage in the DD cohort. We provide preliminary evidence that rs6980093 associates with language and reading (dis)abilities in two independent Italian cohorts. rs6980093 is an intronic SNP, suggesting that it (or a linked variant) modulates phenotypic association via regulation of FOXP2 expression. Because FOXP2 brain expression is finely regulated, both temporally and spatially, it is possible that the two alleles at rs6980093 differentially modulate expression levels in a developmental stage- or brain area-specific manner. This might help explaining the heterozygote advantage effect and the different genetic models in the two cohorts.

Genetic bases of human unique traits

Being human, we possess unique biological features, such as the big brain, upright walking and sophisticated language, which set us apart from our close relatives, the non-human primates since our divergence from the Pan lineage approximately 5 million years ago. Scientists have attempted to solve the mystery of our unique phenotypic traits with approaches from paleoanthropology, anatomy, psychology, behavior and social cognition etc. However, the answers are embedded in our genetic makeup. What are the genetic changes in our genome that make us human? By comparing the genomes of humans and nonhuman primates, scientists have identified a lot of genetic changes that might have contributed to the human-specific traits. These genetic changes work at different genetic levels, including sequence changes in protein-coding genes, gene expression changes, gene losses and gene duplications. Natural selection is the driving force pushing fixation of these genetic changes during human evolution, and they may have important contribution to human’s unique phenotypes. In this review, we mainly discuss the relationship between human-specific phenotypes and genetic changes. We summarize our current findings and understandings of genes with human-specific mutations and their possible functional effects. For example, a set of brain-size regulating genes have been identified and many of them showed strong signatures of Darwinian positive selection during primate evolution and human origin. These human-specific mutations likely work their ways through human brain development and eventually form a large brain. Another fascinating example is the language gene FOXP2 that has two human specific mutations, which may lead to a unique developmental pattern change of the human brain region responsible for human language ability. Furthermore, besides protein coding genes, there are other genetic changes, and many identified fast-evolving regions in the human genome are not located in the coding sequences. Instead they are distributed in regulatory sequences likely involved in gene expression regulation which affect the temporal and spatial pattern of human development. Finally, we introduce the recent advance of technologies that can be used to study the functional outcomes of the human specific mutations. These technologies provide useful tools that may reproduce the scenes of human evolution in the laboratory. The in vitro analysis of humanized iPSCs can to some extend mimic the in vivo development of the human brain. Notably, the newly developed gene editing tools including CRISPR-Cas9 and TALEN are promising in studying the human-specific traits using transgenic animal models, especially the transgenic monkey models which may provide much more mechanistic information than the traditional mouse model. The human-specific genetic changes accumulated during human evolution occurred at different levels, but they must work together to produce the human-specific traits. Future studies may establish the links by figuring out how changes at different genetic levels coordinate with each other to make us human.

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

MicroRNAs (miRNAs) are approximately 22-nucleotide-long, non-coding RNAs that bind to complementary mRNAs with inhibitory effect. An intronic miRNA is embedded in a particular gene called its host gene. Our study focuses on the Homo sapiens intronic miRNA-host gene pair, hsa-miR-3666 and FOXP2. Previous report of co-expression of miR-3666 and FOXP2 indicates possible regulation of FOXP2 functions by miR-3666. However, direct correlation has not been shown yet. Therefore, we took a computational approach to determine if and how such modulation occurs. ChIP-seq identified FOXP2 targets and putative miR-3666 targets showed a significant overlap of 574 common target genes. Functional enrichment analysis of common targets revealed over-representation of KEGG pathways and Gene Ontology modules associated with neurodevelopment. These modules, along with further literature mining and protein-protein interaction analysis of FOXP2 and miR3666 identified several specific genes associated with neurodevelopment and finally integration of transcriptomic expressions data lead to the selection of four models depicting the mechanisms by which miR-3666 can modulate FOXP2 functions. Model 1 illustrates that during neurodevelopment, miR-3666 can directly modulate the functions of FOXP2 through regulation of common targets, such as IGF1 and EFNB2, whereas model 2 shows miR-3666 can also indirectly modulate FOXP2 functions by considering targets that are not common for the intronic miRNA-host gene pair, for example CDH2 and LMO4. This direct and indirect regulation is necessary for precise spatial and temporal expression of genes during neurodevelopment. Models 3 and 4 exhibit mechanisms in which the interactions of miR-3666 and FOXP2 with target genes contribute to the pathogenesis of schizophrenia and autism respectively.

T44 - Is language Impairment in Schizophrenia related to Language Genes?

Background Schizophrenia is considered a language related human specific disease. FOXP2 and CNTNAP2 are genes that have been related to language abnormalities; with FOXP2 additionally showing association with schizophrenia in a limited number of studies. In this study we investigated whether FOXP2 and CNTNAP2 are associated with a) severity of formal thought disorder (FTD) – a core language symptom present in schizophrenia, and b) animal fluency scores – a core language production deficit in schizophrenia; where patients have reduced performance. Methods Genotyping for FOXP2 and CNTNAP2 was completed at rs17137124 and rs7794745. Comprehensive clinical interviews and fluency testing using the one minute animal fluency tests were obtained from 53 schizophrenia patients and 119 healthy controls. Fluency scores representing the number of unique animals delivered in one minute. Formal thought disorder was measured using the Thought, Language and Communication scale with scores ranging from 0 to 4. Results Schizophrenia T-allele carriers (TC & TT) of FOXP2 rs17137124 had reduced fluency (animals) compared to: a) healthy controls and b) compared to CC schizophrenia homozygotes (p=.005): SZ (CC= 23.8, TC=18.4, TT= 13.7) and HC (CC=23.8, TC=24.3, TT=24.9). Further, schizophrenia T-allele carriers had increased FTD (p=.046) (CC=1.8, TC=3.1, TT=3.2). T-allele carriers (TA & TT) of CNTNAP2 rs7794745 in the schizophrenia cohort had reduced semantic fluency: schizophrenia (AA= 19.5, TA=18.8 and TT= 15.7) and health controls (AA=24.7, TA=25.0 and TT=25.0), and increased FTD (AA= 1.2, TA=2.7 and TT= 3.5) although neither of these later two analyses reached significance (p=0.1). The CNTNAP2 result possibly being due to very uneven group sizes, with a small TT group (Ns: AA=17, TA=30 and TT=6). Data collection is continuing. Discussion These preliminary results suggest that genes that have been related to receptive and expressive language skills in healthy humans are associated with common language symptoms in schizophrenia: the FOXP2 gene being highly significant with regards to this association. Given our poor understanding of the aetiology of specific symptoms in schizophrenia this work offers a substantial advance in the field; in addition to improving of understanding of the genetics of language more generally.

The small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma and full-length FOXP1 exert similar oncogenic and transcriptional activity in human B cells.

The forkhead transcription factor FOXP1 is generally regarded as an oncogene in activated B cell-like diffuse large B-cell lymphoma. Previous studies have suggested that a small isoform of FOXP1 rather than full-length FOXP1, may possess this oncogenic activity. Corroborating those studies, we herein show that activated B cell-like diffuse large B-cell lymphoma cell lines and primary activated B cell-like diffuse large B-cell lymphoma cells predominantly express a small FOXP1 isoform, and that the 5′-end of the Foxp1 gene is a common insertion site in murine lymphomas in leukemia virus- and transposon-mediated insertional mutagenesis screens. By combined mass spectrometry, (quantative) reverse transcription polymerase chain reaction/sequencing, and small interfering ribonucleic acid-mediated gene silencing, we determined that the small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma lacks the N-terminal 100 amino acids of full-length FOXP1. Aberrant overexpression of this FOXP1 isoform (ΔN100) in primary human B cells revealed its oncogenic capacity; it repressed apoptosis and plasma cell differentiation. However, no difference in potency was found between this small FOXP1 isoform and full-length FOXP1. Furthermore, overexpression of full-length FOXP1 or this small FOXP1 isoform in primary B cells and diffuse large B-cell lymphoma cell lines resulted in similar gene regulation. Taken together, our data indicate that this small FOXP1 isoform and full-length FOXP1 have comparable oncogenic and transcriptional activity in human B cells, suggesting that aberrant expression or overexpression of FOXP1, irrespective of the specific isoform, contributes to lymphomagenesis. These novel insights further enhance the value of FOXP1 for the diagnostics, prognostics, and treatment of diffuse large B-cell lymphoma patients.

In vivo human adipose-derived mesenchymal stem cell tracking after intra-articular delivery in a rat osteoarthritis model.

BackgroundHuman adipose-derived mesenchymal stem cells (haMSCs) have shown efficacy in treating osteoarthritis (OA) both preclinically and clinically via intra-articular (IA) injection. However, understanding the mode of action of the cell therapy has been limited by cell tracking capability and correlation between the pharmacokinetics of the injected cells and the intended pharmacodynamics effect. This study aims to explore methodology and to understand in vivo biodistribution of clinical-grade haMSCs labeled with fluorescent dye and injected into an immunocompetent OA rat model.MethodshaMSCs labeled with fluorescent dye were investigated for their proliferation and differentiation capabilities. Labeled cells were used to establish detection threshold of a noninvasive biofluorescent imaging system before the cells (2.5 × 106) were injected into a conventional rat OA model induced by medial meniscectomy for 8 weeks. We attempted to reveal the existence of labeled cells in vivo by imaging and a molecular biomarker approach, and to correlate with the in vivo efficacy and physical presence over a follow-up period up to 10 weeks.ResultsIn vitro proliferation and differentiation of haMSCs were not affected by the labeling of DiD dye. Detection thresholds of the labeled cells in vitro and in vivo were determined to be 104 and 105 cells, respectively. When 2.5 × 106 haMSCs were injected into the joints of a rat OA model, fluorescent signals (or >105 cells) lasted for about 10 weeks in the surgical knee joint at the same time as efficacy was observed. Signals in nonsurgical rats only lasted for 4 weeks. The human MSCs were shown to engraft to the rat joint tissues and were proliferative. Human FOXP2 gene was only detected in the knee joint tissue, suggesting limited biodistribution locally to the joints.ConclusionsThe current study represents the first attempt to correlate cell therapy efficacy on OA with the physical presence of the injected haMSCs in the OA model, and demonstrates that human adipose-derived mesenchymal stem cells persisted for 10 weeks locally in the rat joint, coinciding with the efficacy observed. It is postulated that persistence and/or proliferation of the haMSCs in the joint is required in order to exert their functions on promoting joint regeneration and/or cartilage protection, further supporting the safety and feasibility of IA injection of MSCs for the treatment of OA patients.

A Gradualist Scenario for Language Evolution: Precise Linguistic Reconstruction of Early Human (and Neandertal) Grammars.

In making an argument for the antiquity of language, based on comparative evidence, Dediu and Levinson (2013) express hope that some combinations of structural features will prove so conservative that they will allow deep linguistic reconstruction. I propose that the earliest stages of syntax/grammar as reconstructed in Progovac (2015a), based on a theoretical and data-driven linguistic analysis, provide just such a conservative platform, which would have been commanded also by Neandertals and the common ancestor. I provide a fragment of this proto-grammar, which includes flat verb-noun compounds used for naming and insult (e.g., rattle-snake, cry-baby, scatter-brain), and paratactic (loose) combinations of such flat structures (e.g., Come one, come all; You seek, you find). This flat, binary, paratactic platform is found in all languages, and can be shown to serve as foundation for any further structure building. However, given the degree and nature of variation across languages in elaborating syntax beyond this proto-stage, I propose that hierarchical syntax did not emerge once and uniformly in all its complexity, but rather multiple times, either within Africa, or after dispersion from Africa. If so, then, under the uniregional hypothesis, our common ancestor with Neandertals, H. heidelbergensis, could not have commanded hierarchical syntax, but “only” the proto-grammar. Linguistic reconstructions of this kind are necessary for formulating precise and testable hypotheses regarding language evolution. In addition to the hominin timeline, this reconstruction can also engage, and negotiate between, the fields of neuroscience and genetics, as I illustrate with one specific scenario involving FOXP2 gene.

Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c.

Cortico-basal ganglia circuits are critical for speech and language and are implicated in autism spectrum disorder (ASD), in which language function can be severely affected. We demonstrate that in the striatum, the gene, Foxp2, negatively interacts with the synapse suppressor, Mef2C. We present causal evidence that Mef2C inhibition by Foxp2 in neonatal mouse striatum controls synaptogenesis of corticostriatal inputs and vocalization in neonates. Mef2C suppresses corticostriatal synapse formation and striatal spinogenesis, but can, itself, be repressed by Foxp2 through direct DNA binding. Foxp2 deletion de-represses Mef2C, and both intrastriatal and global decrease of Mef2C rescue vocalization and striatal spinogenesis defects of Foxp2-deletion mutants. These findings suggest that Foxp2-Mef2C signaling is critical to corticostriatal circuit formation. If found in humans, such signaling defects could contribute to a range of neurologic and neuropsychiatric disorders.

FOXP2 variants in 14 individuals with developmental speech and language disorders broaden the mutational and clinical spectrum

BackgroundDisruptions of the FOXP2 gene, encoding a forkhead transcription factor, are the first known monogenic cause of a speech and language disorder. So far, mainly chromosomal rearrangements such as translocations...

MicroRNA-190 regulates FOXP2 genes in human gastric cancer

ObjectiveTo investigate how microRNA-190 (miR-190) regulates FOXP2 genes in gastric cancer (GC) cell line SGC7901.MethodsWe identified that miR-190 could target FOXP2 genes by using dual luciferase enzyme assay. Precursor fragment transfection of miR-190 was performed with GC cell line SGC7901 and human gastric mucosal cell line GES-1. miR-190 expression was detected by reverse transcription-polymerase chain reaction (RT-PCR) and FOXP2 protein expression was measured by Western blotting.ResultsFOXP2-3′-untranslated region (UTR) in miR-190 transfection group was significantly decreased as compared with other groups. There were no significant differences in fluorescence signals of FOXP2mut-3′-UTR in each group. Therefore, it was assumed that miR-190 can target FOXP2 genes. Through RT-PCR verification, it was observed that the expression level of miR-190 was significantly higher in GC cell line SGC7901 than in human gastric mucosa cell line GES-1 after transfection with miR-190 mimics. The expression level of miR-190 was significantly higher in GES-1 cells than in SGC7901 cells after transfection with miR-190 inhibitors. Western blotting results showed the expression level of FOXP2 was significantly lower in GC cell line SGC7901 than in GES-1 cells. Compared with blank, mimics control, and inhibitors control groups, the miR-190 mimics group showed significantly enhanced proliferation, migration, and invasion abilities, while miR-190 inhibitors group showed decreased abilities toward proliferation, migration, and invasion (P<0.05). The transcription level of miR-190 and the expression level of FOXP2 in tumor tissues and adjacent normal tissues in GC patients were verified to be consistent with those of cell line experiments.ConclusionUpregulation of miR-190 can lead to downregulation of FOXP2 protein expression. miR-190 may serve as a potential target for GC diagnosis.

Clinical, Genetic, and Biochemical Characteristics of Early-Onset Diabetes in the Finnish Population.

Major advances have been made in the classification and genetics of monogenic diabetes in infancy. The objective of the study was to characterize different forms of diabetes diagnosed during the first year of life. Patients diagnosed with diabetes before the age of 1 year in 10 Finnish hospitals from 1980 to 2014 were included. The study was conducted at Kuopio University Hospital and University of Eastern Finland. Patients were identified through diagnosis-based searches from hospital registries including 93 children, of whom 64 participated. DNA sample for sequencing, serum sample, and medical records interventions were included. Incidence of diabetes during the first year of life, sequencing results, human leukocyte antigen (HLA) genotypes, and islet autoantibodies were measured. The incidence of diabetes diagnosed during the first 12 months was 4.4/100 000/year. Three novel and 11 previously described mutations were found in 22 patients from 15 families in the KCNJ11, ABCC8, INS, GCK, FOXP, STAT3, and RFX6 genes. Positive islet autoantibodies were observed in 40.0% of the patients diagnosed during the first 0-6 months of life vs 70.8% of the patients diagnosed between ages of 7 to 12 months. A total of 85.7% of the patients carrying protective HLA genotypes were mutation-positive compared to 7.7% of the patients having high-risk genotypes (P = .001). Mutations in the K-ATP channel and INS genes were the most common cause of early diagnosed monogenic diabetes. After 6 months of age, patients with diabetes had high HLA risk genotypes and islet autoantibodies, reflecting the autoimmune character of diabetes in that age group.

Knockout of Foxp2 disrupts vocal development in mice.

The FOXP2 gene is important for the development of proper speech motor control in humans. However, the role of the gene in general vocal behavior in other mammals, including mice, is unclear. Here, we track the vocal development of Foxp2 heterozygous knockout (Foxp2+/−) mice and their wildtype (WT) littermates from juvenile to adult ages, and observe severe abnormalities in the courtship song of Foxp2+/− mice. In comparison to their WT littermates, Foxp2+/− mice vocalized less, produced shorter syllable sequences, and possessed an abnormal syllable inventory. In addition, Foxp2+/− song also exhibited irregular rhythmic structure, and its development did not follow the consistent trajectories observed in WT vocalizations. These results demonstrate that the Foxp2 gene is critical for normal vocal behavior in juvenile and adult mice, and that Foxp2 mutant mice may provide a tractable model system for the study of the gene’s role in general vocal motor control.